The present invention generally relates to the field of neurology and neuropharmacology and, more particularly, to the use of partial agonists at the glycine modulatory site of the NMDA receptor to treat cognitive dysfunction in Parkinson""s disease and in schizophrenia.
The potential role of glutamatergic drugs in the treatment of Parkinson""s disease (PD) has received considerable interest in the last several years. The popular theory of basal ganglia circuitry proposes that basal ganglia output neurons in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) are regulated in part by glutamatergic inputs from the subthalamic nucleus. (Albin R L, Young A B, Penny J B. The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366-375, 1989). Overactivity of these subthalamic glutamatergic projections are believed to result in excessive inhibition of thalamic neurons that receive GPi and SNr inputs and underlies expression of parkinsonian motor signs. (Albin et al., 1989). Based on this, it has been suggested that treatment with glutamate antagonist drugs might have beneficial anti-Parkinson actions. (Greenamyre J T, Eller R V, Zhang Z, Ovadia A, Kurlan R, Gash D M. Antiparkinson effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson""s disease. Ann Neurol 35:655-661, 1994). Indeed, the non-competitive NMDA antagonist MK-801 has been shown to increase locomotion in dopamine-depleted rats (Klockgether T, Turski L. NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats. Ann Neurol 28:539-546, 1990) and reverse neuroleptic-induced catalepsy in rats (Schmidt W J, Bubser M. Anticataleptic effects of the N-methyl-D-aspartate antagonist MK-801 in rats. Pharmacol Biochem Behav 32:621-623, 1989). In addition, stereotaxic administration of glutamate antagonists into the GPi or SNr ameliorated parkinsonian features in 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. (Brotchie J M, Mitchell U, Sambrook M A, Crossman A R. Alleviation of parkinsonism by antagonism of excitatory amino acid transmission in the medial segment of the globus pallidus in rat and primate. Mov Disord 6:133-138, 1991; Klockgether T, Turski L, Honore T, Zhang Z M, Gash D M, Kurlan R, Greenamyre J T. The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine depleted rats and MPTP treated monkeys. Ann Neurol 30:717-723, 1991).
However, several studies utilizing systemically administered NMDA antagonists to parkinsonian monkeys have not had the predicted anti-Parkinson effect. Many studies have shown that administration of MK-801 to parkinsonian monkeys either has no effect or exacerbates the parkinsonian features (Crosssman A R, Peggs D, Boyce S, Luquin M R, Sambrook M A. Effect of the NMDA atagonist MK-801 on MPTP-induced parkinsonism in the monkey. Neuropharmacol 11:1271-1273, 1989; Rupniak N M J, Duchnowski M, Tye S J, Cook G, Iversen S D. Failure of D-cycloserine to reverse cognitive disruption induced by scopolamine or phencyclidine in primates. Life Sci 50:1959-1962, 1992). Additionally, while some studies claim that glutamate antagonists potentiate levodopa responses in parkinsonian monkeys (Greenamyre et al., 1994), others have shown antagonistic effects on levodopa and dopamine agonist-induced functional improvements. (Crosssman et al., 1989; Rupniak N M J, Boyce S, Steventon M J, Iversen S D, Marsden CD. Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys. Ann Neurol 32:103-105, 1992; Domino E F, Sheng J. N-methyl-D-aspartate receptor antagonist and dopamine D1 and D2 agonist interactions in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced hemiparkinsonian monkeys. J Pharmacol Exp Ther 264:221-225, 1993).
Although it is still unclear as to the therapeutic usefulness of NMDA antagonists in treating the motor dysfunctions of PD, there may be a role for stimulation of the NMDA receptor in treating some of the cognitive sequelae of PD. Several reports have suggested that positive modulation of the NMDA receptor might be useful for the treatment of various learning and memory impairments. Activation of the NMDA receptor leads to long-term potentiation (a mechanism of synaptic modification related to memory formation and learning) (Collingridge G L, Bliss T V P (1987) NMDA receptors-their role in long-term potentiation. Trends Neurosci 10:288-293, 1987) and antagonism of NMDA receptors results in disruption of learning and memory processes. (Bischoff C, Tiedtke P I. Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks. Eur J Pharmacol 213:269-273, 1992; Ogura H, Aigner T G. MK-801 impairs recognition memory in rhesus monkeys: comparison with cholinergic drugs. J Pharmacol Exp Ther 266:60-64, 1993). While potentiating glutamatergic neurotransmission at the NMDA receptor might improve certain cognitive functions, it may also lead to exctitoxicity and cell death.
In the present invention, use of a partial agonist at the glycine modulatory site of the NMDA receptor can circumvent the problem of excitotoxicity while allowing NMDA receptor activation. The glycine-B site on the NMDA receptor is a modulatory site wherein glycine, in the presence of glutamate, acts synergistically with glutamate to promote channel opening and excitatory neurotransmission. One such partial glycine agonist is the antibiotic D-cycloserine. Other such partial glycine agonists include D-serine and serine racemase, the enzyme that converts L-serine to D-serine, thereby promoting endogenous biosynthesis of a partial glycine agonist.
As a partial agonist, D-cycloserine, at low concentrations, acts as an agonist mimicking glycine""s effects and stimulating NMDA receptors. (Watson G B, Bolanowski M A, Baganoff M P, Deppeler C L, Lanthorn T H. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed Xenopus oocytes. Brain Res 510:158-160, 1990; Lanthorn T H. d-Cycloserine: agonist turned antagonist. Amino Acids 6:247-260, 1994). At high concentrations, it can antagonize the effects of endogenous glycine, blocking excess stimulation. The present invention demonstrates activation of the glycine/NMDA receptor complex by D-cycloserine to improve cognitive deficits, including those present in Parkinson""s disease and in schizophrenia. As noted above, D-serine and serine racemase may also be used in the present invention.
The present invention also involves the combination of D-serine and/or other partial glycine agonists with existing anti-Parkinsonian treatments (such as levodopa/carbidopa and dopamine agonists) to treat Parkinson""s disease. While existing treatments enhance motor functioning in Parkinson""s patients, they do little to enhance cognitive functioning and, in fact, may worsen cognitive functioning. By combining the partial glycine agonists with existing anti-Parkinsonian treatments, motor and cognitive function in Parkinson""s patients can be enhanced, thereby providing a better overall therapeutic effect than with either compound alone.
Definitions
xe2x80x9cPartial glycine agonistxe2x80x9d means D-serine, serine racemase, D-cycloserine, or another compound that can act functionally like or mimic the action of a partial glycine agonist.
Accordingly, it is an object of the present invention to provide a method of treating cognitive dysfunction in a mammal having Parkinson""s disease, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor lex of said mammal.
It is a further object of the present invention to provide a method of treating cognitive dysfunction in a mammal having Parkinson""s disease, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor complex of said mammal, wherein said partial glycine agonist is at least one of the group of D-cycloserine, D-serine, and serine racemase.
It is another object of the present invention to provide a method of treating cognitive dysfunction in a mammal having schizophrenia, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor complex of said mammal.
It is a further object of the present invention to provide a method of treating cognitive dysfunction in a mammal having schizophrenia, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor complex of said mammal, wherein said partial glycine agonist is at least one of the group of D-cycloserine, D-serine, and serine racemase.
It is another object of the present invention to provide a method of treating cognitive dysfunction and motor dysfunction in a mammal having Parkinson""s disease, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor complex of said mammal in combination with at least one of the group of levodopa/carbidopa and a dopamine agonist.
It is a further object of the present invention to provide a method of treating cognitive dysfunction and motor dysfunction in a mammal having Parkinson""s disease, comprising administering a therapeutically effective amount of a partial glycine agonist to the glycine modulatory site of the NMDA receptor complex of said mammal in combination with at least one of the group of levodopa/carbidopa and a dopamine agonist, wherein said partial glycine agonist is at least one of the group of D-cycloserine, D-serine, and serine racemase.